| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| A model for demonstration of reversal of impairment of endothelium-dependent relaxation in the cholesterol-fed rabbit Kappagoda, C. T., A. B. Thomson, et al. (1990), Can J Physiol Pharmacol 68(7): 845-50. Abstract: This investigation was undertaken to determine whether it was possible to restore endothelium-dependent relaxation (EDR) in the cholesterol-fed rabbit model of atherosclerosis following discontinuation of the cholesterol. New Zealand white rabbits, approximately 8 weeks of age, were randomized into (i) control group (9 animals fed a standard rabbit diet) and (ii) experimental group (27 animals: fed the same diet supplemented with 2.5% cholesterol). The experimental animals were restored to the standard diet after 3 weeks. EDR to acetylcholine (-9.0 to -5.0 log mol/L) was examined in the experimental animals at 3, 7, and 15 weeks after commencement of the study (n = 9 at each stage) and the nine control animals examined after 7 weeks. At the end of 7 weeks, EDR to acetylcholine (-6.0 log mol/L) was significantly (p less than 0.05) impaired in the experimental group (34.3 +/- 3.8%) compared with that in the control group (79.8 +/- 3.0%). The loss of EDR was not apparent in the experimental group at 3 weeks (relaxation: 81.7 +/- 4.7%). At the end of 15 weeks, the EDR was significantly restored in the experimental group (relaxation: 63.6 +/- 5.1%). These findings demonstrate that it is possible to reverse the loss of EDR that occurs with cholesterol feeding in the rabbit by limiting the period of exposure to a high cholesterol diet. |
| A model to assess the cost effectiveness of statins in achieving the UK National Service Framework target cholesterol levels Wilson, K., J. Marriott, et al. (2003), Pharmacoeconomics 21 Suppl 1: 1-11. Abstract: BACKGROUND: Coronary heart disease (CHD) is a public health priority in the UK. The National Service Framework (NSF) has set standards for the prevention, diagnosis and treatment of CHD, which include the use of cholesterol-lowering agents aimed at achieving targets of blood total cholesterol (TC) < 5.0 mmol/L and low density lipoprotein-cholesterol (LDL-C) < 3.0 mmol/L. In order to achieve these targets cost effectively, prescribers need to make an informed choice from the range of statins available. AIM: To estimate the average and relative cost effectiveness of atorvastatin, fluvastatin, pravastatin and simvastatin in achieving the NSF LDL-C and TC targets. DESIGN: Model-based economic evaluation. METHODS: An economic model was constructed to estimate the number of patients achieving the NSF targets for LDL-C and TC at each dose of statin, and to calculate the average drug cost and incremental drug cost per patient achieving the target levels. The population baseline LDL-C and TC, and drug efficacy and drug costs were taken from previously published data. Estimates of the distribution of patients receiving each dose of statin were derived from the UK national DIN-LINK database. RESULTS: The estimated annual drug cost per 1000 patients treated with atorvastatin was pound 289000, with simvastatin pound 315000, with pravastatin pound 333000 and with fluvastatin pound 167000. The percentages of patients achieving target are 74.4%, 46.4%, 28.4% and 13.2% for atorvastatin, simvastatin, pravastatin and fluvastatin, respectively. Incremental drug cost per extra patient treated to LDL-C and TC targets compared with fluvastatin were pound 198 and pound 226 for atorvastatin, pound 443 and pound 567 for simvastatin and pound 1089 and pound 2298 for pravastatin, using 2002 drug costs. CONCLUSIONS: As a result of its superior efficacy, atorvastatin generates a favourable cost-effectiveness profile as measured by drug cost per patient treated to LDL-C and TC targets. For a given drug budget, more patients would achieve NSF LDL-C and TC targets with atorvastatin than with any of the other statins examined. |
| A modified theta-toxin produced by limited proteolysis and methylation: a probe for the functional study of membrane cholesterol Ohno-Iwashita, Y., M. Iwamoto, et al. (1990), Biochim Biophys Acta 1023(3): 441-8. Abstract: A derivative of cytolytic theta-toxin from Clostridium perfringens was prepared by limited proteolytic digestion of the native toxin followed by methylation. Among the chloroform/methanol-extractable, lipid components of sheep and human erythrocytes, the proteinase-nicked and methylated derivative (MC theta) specifically binds to cholesterol. While MC theta retains binding affinity comparable to that of intact toxin, it causes no obvious membrane damage, resulting in no hemolysis at temperatures of 37 degrees C or lower. Using MC theta, we demonstrated the possible existence of high- and low-affinity sites for theta-toxin on sheep erythrocytes at both 37 degrees C and 10 degrees C. The number of high-affinity sites on sheep erythrocytes was estimated to be approximately 3-times larger at 37 degrees C than that at 10 degrees C. In addition, high- and low-affinity sites were demonstrated in human erythrocytes and a lymphoma B cell line, BALL-1 cells. Both binding sites disappear upon simultaneous treatment of cells with sublytic doses of digitonin, suggesting that cholesterol is an essential component of both the high- and low-affinity sites and that the mode of cholesterol existence in plasma membranes is heterogeneous in these cells. Because of its high affinity for membrane cholesterol without causing any obvious membrane changes at physiological temperatures, MC theta may provide a probe for use in the functional study of membrane cholesterol. |
| A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity Funke, H., A. von Eckardstein, et al. (1991), Proc Natl Acad Sci U S A 88(11): 4855-9. Abstract: Epidemiological as well as biochemical evidence of recent years has established that a low plasma level of high density lipoprotein-cholesterol is a predictor for the risk of coronary artery disease. However, there is a heterogeneous group of rare familial disorders, characterized by severe high density lipoprotein deficiency, in which the predicted increased risk is not clearly apparent. One such disorder has been called fish eye disease to reflect the massive corneal opacification seen in these patients. In this report, we describe the biochemical and genetic presentation of two German fish eye disease homozygotes and their family members. Vertical transmission of a decrease in the specific activity of lecithin-cholesterol acyltransferase (EC 2.3.1.43) indicated that this enzyme was a candidate gene for harboring the defect responsible for this disorder. Direct sequencing of DNA segments amplified by the polymerase chain reaction (PCR) that encode the exons of the lecithin-cholesterol acyltransferase gene led to the identification of a homozygous mutation resulting in the substitution of threonine at codon 123 for an isoleucine residue in both individuals. Family analysis in an extended pedigree was used to establish a causal relationship between this mutation and the biochemical phenotype for fish eye disease. The homozygous presence of this mutation in two phenotypically homozygous members of an unrelated Dutch family with fish eye disease further supports this finding. |
| A molecular defect in hepatic cholesterol biosynthesis in sitosterolemia with xanthomatosis Nguyen, L. B., S. Shefer, et al. (1990), J Clin Invest 86(3): 923-31. Abstract: We examined the relationship between cholesterol biosynthesis and total and high affinity LDL binding in liver specimens from two sitosterolemic and 12 healthy control subjects who died unexpectedly and whose livers became available when no suitable recipient for transplantation was identified. Accelerated atherosclerosis, unrestricted intestinal sterol absorption, increased plasma and tissue plant sterol concentrations, and low cholesterol synthesis characterize this disease. Mean total microsomal HMG-CoA reductase (rate-control controlling enzyme for cholesterol biosynthesis) activity was sevenfold higher (98.1 +/- 28.8 vs. 15.0 +/- 2.0 pmol/mg protein per min) and microsomal enzyme protein mass was eightfold larger (1.43 +/- 0.41 vs. 0.18 +/- 0.04 relative densitometric U/mg protein) in 11 controls than the average for two sitosterolemic liver specimens. HMG-CoA reductase mRNA probed with pRED 227 and pHRED 102 was decreased to barely detectable levels in the sitosterolemic livers. In addition, there was a 50% decrease in the rate 2-14Cmevalonic acid was converted to cholesterol by sitosterolemic liver slices compared with controls (112 vs. 224 +/- 32 pmol/g liver per h). In contrast, average total LDL binding was 60% greater (326 vs. 204 +/- 10 ng/mg), and high affinity (receptor-mediated) binding 165% more active (253 vs. 95.1 +/- 8.2 ng/mg) in two sitosterolemic liver membrane specimens than the mean for 12 controls. Liver morphology was intact although sitosterolemic hepatocytes and microsomes contained 24 and 14% less cholesterol, respectively, and 10-100 times more plant sterols and 5 alpha-stanols than control specimens. We postulate that inadequate cholesterol biosynthesis is an inherited abnormality in sitosterolemia and may be offset by augmented receptor-mediated LDL catabolism to supply cellular sterols that cannot be formed. |
| A monogalactosylated cholesterol derivative that specifically induces uptake of LDL by the liver Bijsterbosch, M. K., H. F. Bakkeren, et al. (1992), Arterioscler Thromb 12(10): 1153-60. Abstract: We described earlier the effect of tris-gal-chol (a triantennary galactose structure coupled to cholesterol) on the fate of low density lipoprotein (LDL) and high density lipoprotein (HDL). Tris-gal-chol-loaded LDL and HDL are both efficiently cleared from blood by hepatic galactose-specific receptors. Thus, tris-gal-chol combines a beneficial LDL-reducing effect with an equally effective but undesirable HDL-lowering effect. We recently synthesized a cholesterol derivative with a single terminal galactose residue, denoted mono-gal-chol. In the present study we show that this compound, which incorporates readily into both LDL and HDL, induces rapid association of LDL and HDL to the liver. The mono-gal-chol-stimulated hepatic association of HDL, however, was about fivefold lower than that of LDL. In the liver, Kupffer cells were mainly (90%) responsible for the liver uptake of mono-gal-chol-loaded LDL, whereas the complex of mono-gal-chol with HDL was predominantly (95%) taken up by parenchymal cells. Uptake by both cell types proceeded via galactose-specific receptors and was followed by degradation of the apolipoproteins in the lysosomes. Thus, compared with tris-gal-chol, mono-gal-chol is equally effective in the induction of galactose-specific uptake of LDL by Kupffer cells. However, the galactose-specific receptor on parenchymal cells recognizes mono-gal-chol-loaded HDL less efficiently than tris-gal-chol-containing HDL. These results indicate that mono-gal-chol might be used to specifically lower LDL levels in patients with a high LDL cholesterol level. |
| A more valid measurement of low-density lipoprotein cholesterol in diabetic patients Hirany, S., D. Li, et al. (1997), Am J Med 102(1): 48-53. Abstract: PURPOSE: This study was conducted to determine if the direct low-density lipoprotein (LDL) cholesterol assay would provide a more valid measure of LDL cholesterol in diabetic patients compared with the Friedewald equation. PATIENTS AND METHODS: Fasting plasma from 148 diabetic patients, 40 with insulin-dependent diabetes (IDDM) and 108 with non-insulin dependent diabetes (NIDDM) with triglyceride levels < 400 mg/dL, were analyzed for LDL cholesterol using the Friedewald equation, the direct LDL assay, and beta-quantification. Forty-six diabetic patients with triglyceride levels > or = 400 mg/dL were also studied to determine the validity of the direct LDL cholesterol assay with hypertriglyceridemia. RESULTS: The friedewald equation and the direct LDL cholesterol assay correlated well with beta-quantification (r = 0.969 and r = 0.971, respectively) for LDL cholesterol determination in diabetic patients. Although the Friedewald equation in comparison with beta-quantification underestimated (8%) LDL cholesterol values in diabetic patients, the direct LDL cholesterol assay had a mean bias of < 1%. Also, the underestimation by the Friedewald equation exceeded 10% for the triglyceride subgroup of 200 to 400 mg/dL. Furthermore, the accuracy of the direct LDL cholesterol assay was superior to the Friedewald equation since LDL cholesterol levels determined by the two methods coincided within +/- 10% of beta-quantification in 85% and 68% of diabetic patients, respectively (P = 0.0005). Similar results for both the Friedewald equation and the direct LDL cholesterol assay in comparison with beta-quantification were seen when diabetic patients were subgrouped into IDDM and NIDDM. Also, the direct LDL cholesterol assay appeared to provide a reliable estimate in patients with triglycerides > or = 400 mg/dL. CONCLUSION: The results of our studies indicate that the direct LDL cholesterol assay is a more reliable and accurate method than the Friedewald formula for LDL cholesterol determination in diabetic patients and is more rapid and cost effective than the reference method. |
| A mouse model of human familial hypercholesterolemia: markedly elevated low density lipoprotein cholesterol levels and severe atherosclerosis on a low-fat chow diet Powell-Braxton, L., M. Veniant, et al. (1998), Nat Med 4(8): 934-8. Abstract: Mutations in the low density lipoprotein (LDL) receptor gene cause familial hypercholesterolemia, a human disease characterized by premature atherosclerosis and markedly elevated plasma levels of LDL cholesterol and apolipoprotein (apo) B100. In contrast, mice deficient for the LDL receptor (Ldlr-/-) have only mildly elevated LDL cholesterol levels and little atherosclerosis. This difference results from extensive editing of the hepatic apoB mRNA in the mouse, which limits apoB100 synthesis in favor of apoB48 synthesis. We have generated Ldlr-/- mice that cannot edit the apoB mRNA and therefore synthesize exclusively apoB100. These mice had markedly elevated LDL cholesterol and apoB100 levels and developed extensive atherosclerosis on a chow diet. This authentic model of human familial hypercholesterolemia will provide a new tool for studying atherosclerosis. |
| A mouse model of sitosterolemia: absence of Abcg8/sterolin-2 results in failure to secrete biliary cholesterol Klett, E. L., K. Lu, et al. (2004), BMC Med 2: 5. Abstract: BACKGROUND: Mutations in either of two genes comprising the STSL locus, ATP-binding cassette (ABC)-transporters ABCG5 (encoding sterolin-1) and ABCG8 (encoding sterolin-2), result in sitosterolemia, a rare autosomal recessive disorder of sterol trafficking characterized by increased plasma plant sterol levels. Based upon the genetics of sitosterolemia, ABCG5/sterolin-1 and ABCG8/sterolin-2 are hypothesized to function as obligate heterodimers. No phenotypic difference has yet been described in humans with complete defects in either ABCG5 or ABCG8. These proteins, based upon the defects in humans, are responsible for regulating dietary sterol entry and biliary sterol secretion. METHODS: In order to mimic the human disease, we created, by a targeted disruption, a mouse model of sitosterolemia resulting in Abcg8/sterolin-2 deficiency alone. Homozygous knockout mice are viable and exhibit sitosterolemia. RESULTS: Mice deficient in Abcg8 have significantly increased plasma and tissue plant sterol levels (sitosterol and campesterol) consistent with sitosterolemia. Interestingly, Abcg5/sterolin-1 was expressed in both liver and intestine in Abcg8/sterolin-2 deficient mice and continued to show an apical expression. Remarkably, Abcg8 deficient mice had an impaired ability to secrete cholesterol into bile, but still maintained the ability to secrete sitosterol. We also report an intermediate phenotype in the heterozygous Abcg8+/- mice that are not sitosterolemic, but have a decreased level of biliary sterol secretion relative to wild-type mice. CONCLUSION: These data indicate that Abcg8/sterolin-2 is necessary for biliary sterol secretion and that loss of Abcg8/sterolin-2 has a more profound effect upon biliary cholesterol secretion than sitosterol. Since biliary sitosterol secretion is preserved, although not elevated in the sitosterolemic mice, this observation suggests that mechanisms other than by Abcg8/sterolin-2 may be responsible for its secretion into bile. |
| A multicenter, randomized, double-blind clinical trial comparing the low-density lipoprotein cholesterol-lowering ability of lovastatin 10, 20, and 40 mg/d with fluvastatin 20 and 40 mg/d Davidson, M. H., J. Palmisano, et al. (2003), Clin Ther 25(11): 2738-53. Abstract: BACKGROUND: The available statin drugs have similar pharmacodynamic properties but are not equal in low-density lipoprotein cholesterol (LDL-C)-lowering efficacy. OBJECTIVE: The aim of this study was to compare the effects of lovastatin and fluvastatin in lowering LDL-C. METHODS: This was a prospective, randomized, double-blind study of patients aged >20 years with primary hypercholesterolemia conducted at 44 clinical sites across the United States. After a 6-week National Cholesterol Education Program (NCEP) Step I diet lead-in period in patients taking lipid-lowering drugs at screening, patients were randomized to receive lovastatin 10, 20, or 40 mg/d or fluvastatin 20 or 40 mg/d (the doses available at the time the study was conducted) for 6 weeks. Patients not taking lipid-lowering drugs at screening and who had been following the Step I diet for at least 6 weeks proceeded to the treatment phase. All patients received instruction for a Step I diet, which they followed throughout the treatment phase. After the treatment period, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), LDL-C, and triglycerides were measured, and TC:HDL-C and LDL-C:HDL-C ratios were calculated. RESULTS: A total of 838 patients (476 men, 362 women; mean SD age, 59 12 years) were included in the study. Lovastatin 20 and 40 mg/d significantly reduced mean LDL-C compared with the same dosages of fluvastatin. TC and the LDL-C:HDL-C ratio decreased more with lovastatin than with fluvastatin at a given dose level. Approximately 50% of patients treated with lovastatin 20 and 40 mg/d compared with approximately 25% treated with fluvastatin 20 and 40 mg/d reached NCEP Adult Treatment Panel II LDL-C goals. CONCLUSION: In this small study population of patients with primary hypercholesterolemia taking lipid-lowering drugs, short-term (6-week) treatment with lovastatin was more efficacious than fluvastatin in lowering cholesterol levels and reaching LDL-C treatment goals. |
| A multi-centre evaluation of the measurement of high density lipoprotein cholesterol by the Reflotron assay Bijster, P. (1993), Eur J Clin Chem Clin Biochem 31(3): 173-8. Abstract: A multi-centre study was undertaken to evaluate the performance of the Reflotron high density lipoprotein cholesterol method in twelve different clinical chemistry hospital laboratories. Results were compared with phosphotungistic acid/Mg2+ and polyethylene glycol/dextran sulphate/Mg2+ precipitation methods, routinely performed in these laboratories. Precision was found to be excellent, for both the day-to-day results (SD = 0.03 mmol/l) and for the overall between-laboratory precision (SD = 0.02 mmol/l), measured with control sera. HDL cholesterol concentrations measured with the Reflotron system were about 10% lower than those obtained with the two routine precipitation methods, using different instruments with different cholesterol standardization procedures. |
| A multicentre, hospital study of the efficacy and safety of terazosin and its effects on the plasma cholesterol levels of patients with essential hypertension Lytle, T. B., S. J. Coles, et al. (1991), J Clin Pharm Ther 16(4): 263-73. Abstract: The safety, efficacy and the effect on the plasma total cholesterol of once-daily terazosin hydrochloride administered either as monotherapy or in combination with other antihypertensive therapy were evaluated in patients with mild-moderate uncontrolled essential hypertension in this U.K., open, multicentre hospital, 3-month study. Patients initially received 1 mg of terazosin as monotherapy or in addition to their current antihypertensive therapy followed by dose titration, if necessary, to a maximum of 10 mg over the first 6 weeks depending upon blood pressure control. Patients then continued treatment for a further 6 weeks on their optimum dosage. There were highly significant mean reductions in systolic and diastolic blood pressures at the end of 12 weeks for 439 patients of 18.5 and 14.0 mmHg (P less than 0.001), respectively, and were similar to the reductions shown when subgrouping the patients into either those 197 patients who were treated with terazosin as monotherapy (17.6/13.7 mmHg, P less than 0.001) or those 242 patients treated with terazosin in combination with other antihypertensive agents (19.3/14.2 mmHg, P less than 0.001). In addition, in a sub-group of 132 patients who had their mean total cholesterol measured at the end of 12 weeks' treatment, there was a significant reduction of -0.4 mmol/l (P less than 0.01). A similar significant mean reduction for total cholesterol was also shown when this subgroup was divided into those 50 patients who were treated with terazosin as monotherapy (-0.56 mmol/l, P less than 0.01), but not for those 82 patients treated with terazosin in combination with other antihypertensive agents (-0.3 mmol/l, P greater than 0.05 less than 0.1). No serious toxicity or safety problems were observed. Once daily administration of terazosin, either as monotherapy or in combination with other antihypertensive agents, proved to be safe and effective in reducing the blood pressure of patients with uncontrolled mild-moderate essential hypertension and favourably reduced the total plasma cholesterol level. |
| A multicentre, hospital study of the efficacy and safety of terazosin and its effects on the plasma cholesterol levels of patients with untreated essential hypertension Lytle, T., S. Coles, et al. (1991), J Hum Hypertens 5(1): 35-8. Abstract: The safety, efficacy and the effect on the plasma total cholesterol of once-daily terazosin hydrochloride administered as monotherapy was evaluated in 69 patients with mild-moderate untreated essential hypertension in this open, hospital, multi-centre, 3 month study. Patients initially received 1 mg of terazosin followed by dose titration, if necessary, to a maximum of 10 mg over the first six weeks depending upon blood pressure control. Patients then continued treatment for a further six weeks on their optimum dosage. At the end of 12 weeks' treatment, there were highly significant mean reductions in systolic and diastolic blood pressures of 14.5 and 12.9 mmHg (P less than 0.001), respectively, as well as a significant reduction in the mean total cholesterol of -0.56 mmol/l (-9.5%, P less than 0.01). No serious toxicity or safety problems were observed. Once daily administration of terazosin proved to be safe and effective in reducing the blood pressure of patients with mild-moderate essential hypertension and favourably reduced the total plasma cholesterol level. |
| A multinuclear solid-state NMR study of phospholipid-cholesterol interactions. Dipalmitoylphosphatidylcholine-cholesterol binary system Guo, W. and J. A. Hamilton (1995), Biochemistry 34(43): 14174-84. Abstract: Multinuclear (1H, 13C, 31P) MASNMR and static solid-state 31P NMR were used to study the molecular interactions between dipalmitoylphosphatidylcholine (DPPC) and free cholesterol (CHOL) in multilayers of DPPC containing 0-65 mol % CHOL with respect to total lipid at temperatures between 25 and 55 degrees C. 13C chemical shifts and line shapes for DPPC and CHOL resonances were measured in 13C MASNMR spectra. The apparent chemical shift anisotropy (CSA) of the DPPC acyl methylene resonances (CH2)n was calculated from the 1H MASNMR spectra. CSA and line shape changes were recorded as a function of CHOL content by 31P static solids and MASNMR. The presence of CHOL significantly changed the 13C chemical shifts and line shapes of DPPC carbonyl carbons below or above the main transition temperature of pure DPPC. Chemical shift changes were also observed for CHOL carbons as a function of the mixing ratio, signifying a changing local environment of CHOL. For mixtures with CHOL > 50 mol %, 13C MASNMR detected crystalline CHOL in the monohydrate form. When the excess CHOL was in a submicroscopic crystalline form that was not readily detected by differential scanning calorimetry, or optical microscopy (but readily observed by 13C MASNMR), the 31P powder pattern was affected, suggesting interaction of the excess CHOL with the aqueous interface of the bilayer. These results suggest the potential of 13C MASNMR for detection of crystalline CHOL in biological samples. |
| A mutant GTPase affects the efficiency of cholesterol transfer from cells to lipoprotein acceptors Vieira, A. (2001), Mol Genet Metab 74(3): 399-402. |
| A natural apolipoprotein A-I variant, apoA-I (L141R)Pisa, interferes with the formation of alpha-high density lipoproteins (HDL) but not with the formation of pre beta 1-HDL and influences efflux of cholesterol into plasma Miccoli, R., Y. Zhu, et al. (1997), J Lipid Res 38(6): 1242-53. Abstract: ApoA-I(L141R)Pisa is a naturally occurring apolipoprotein A-I variant that causes virtual absence of HDL in hemizygotes and hypoalphalipoproteinemia with half-normal levels of HDL-cholesterol in heterozygotes. In this study we analyzed the distribution of HDL subclasses in plasmas of four hemizygotes for this mutation. We also investigated the abilities of these plasmas to esterify cholesterol and to promote cholesterol efflux. Residual apoA-I-containing lipoproteins in plasmas of hemizygotes for apoA-I(L141R)Pisa correspond to pre beta 1-LpA-I and small alpha-LpA-I. Unlike normal pre beta 1-LpA-I, pre beta 1-LpA-I of apoA-I(L141R)Pisa hemizygotes was not converted into a larger alpha-migrating particle. Plasmas of apoA-I(L141R)Pisa hemizygotes were significantly reduced in their activity to esterify cholesterol in either endogenous or exogenous lipoproteins. Cholesterol efflux capacity was significantly lower than that of normal plasma. Efflux of 3H cholesterol from radiolabeled fibroblasts into apoB-depleted plasma of normal probands was biphasic with fast cholesterol efflux occurring in the first minute. Thereafter, cholesterol efflux was slow and unsaturable. After incubation with radiolabeled fibroblasts, efflux values of 3Hcholesterol into apoB-depleted plasma from normal controls and from apoA-I(L141R)Pisa hemizygotes were indistinguishable at 1 min. Longer incubations with apoB-free plasma from apoA-I(L141R)Pisa hemizygotes did not, however, lead to the unsaturable increase in cholesterol efflux that was observed during incubations with apoB-free plasma of normolipidemic probands. Pre beta 1-LpA-I of apoA-I(L141R)Pisa hemizygotes took up significantly less cell-derived 3Hcholesterol than pre beta 1-LpA-I of normal donors. We conclude that apoA-I(L141R)Pisa interferes with the formation of lipid-rich alpha-HDL but not with that of lipid-poor pre beta 1-LpA-I. Very low concentrations of alpha-HDL in plasmas of apoA-I(L141R)Pisa hemizygotes combined with reduced LCAT activity cause a decrease of the slow, unspecific, and LCAT-dependent components of cholesterol efflux into plasma. |
| A natural product that lowers cholesterol as an antagonist ligand for FXR Urizar, N. L., A. B. Liverman, et al. (2002), Science 296(5573): 1703-6. Abstract: Extracts of the resin of the guggul tree (Commiphora mukul) lower LDL (low-density lipoprotein) cholesterol levels in humans. The plant sterol guggulsterone 4,17(20)-pregnadiene-3,16-dione is the active agent in this extract. We show that guggulsterone is a highly efficacious antagonist of the farnesoid X receptor (FXR), a nuclear hormone receptor that is activated by bile acids. Guggulsterone treatment decreases hepatic cholesterol in wild-type mice fed a high-cholesterol diet but is not effective in FXR-null mice. Thus, we propose that inhibition of FXR activation is the basis for the cholesterol-lowering activity of guggulsterone. Other natural products with specific biologic effects may modulate the activity of FXR or other relatively promiscuous nuclear hormone receptors. |
| A new ABCA1 mutation associated with low HDL cholesterol but without coronary artery disease Kolovou, G., K. Anagnostopoulou, et al. (2003), Atherosclerosis 169(2): 345-6; author reply 347-8. |
| A new approach for the detection of type III hyperlipoproteinemia by RLP-cholesterol assay Nakajima, K., T. Saito, et al. (1994), J Atheroscler Thromb 1(1): 30-6. Abstract: Type III is a remnant hyperlipoproteinemia identified by the presence of beta-VLDL (remnant lipoprotein) as well as a genetic variant of apo E (apo E2/2). The RLP isolated from the serum of Type III patients by a new method we have developed, the RLPcholesterol assay, was identified as chylomicron and VLDL remnant. In addition, the RLP-C levels of the Type III patients were significantly higher than other hyperlipidemic patients with similar serum TG levels, while the ratio of TC/TG in RLP-C of both groups was not significantly different. The RLP-cholesterol assay appears to be useful for the screening and monitoring of Type III hyperlipoproteinemia when used in conjunction with the assays of serum TG level and genetic apo E isoform analysis. |
| A new approach to cholesterol Bzduch, V., D. Behulova, et al. (2001), Cas Lek Cesk 140(22): 685-7. Abstract: Although much is known about hypercholesterolemia and the associated risk for the development of atherosclerosis, very little research has focused on altered cholesterol biosynthesis. Recent discovery that the biochemical basis for the human malformation syndrome, Smith-Lemli-Opitz syndrome appears to lie in altered cholesterol biosynthesis has changed this situation. Cholesterol has an extraordinary important functions in organism. Recommendations to lower serum cholesterol are widespread, yet low serum cholesterol is associated with poorly understood morbidity. Cholesterol is still an enigmatic, essential metabolite and much remains to learn about it. |